Epidemiologic studies have demonstrated correlations of dietary intake of total and saturated fats with the incidence of atherosclerosis both within and between populations. However, only a small fraction of the population appears to be susceptible to diet-induced atherosclerosis. We have undertaken the investigation of human intestinal apolipoprotein gene expression to evaluate one potential molecular mechanism for this phenomenon. There is one human apolipoprotein B gene present on chromosome 2. Two distinct proteins are derived from this gene by a novel posttranscriptional modification. After transcription, the cytosine at residue 6666 is converted to a uridine. This changes the codon from that of a glutamine to a stop codon. Thus, the mRNA can code for a full length protein termed apoB-100 as well as the prematurely terminated apoB-48. The human liver produces only apoB-100 and the human intestine synthesizes primarily apoB-48. We have previously established that 7% of the apoB synthesized by the human intestine is apoB-100. Since the plasma half- life of apoB-48 is < 15 minutes and apoB-100 more than 2 days, production of enterocytically-derived apoB-100 could lead to triglyceride-rich, long- lived, atherogenic lipoprotein particles that could be influenced by diet. Utilizing intestinal biopsies obtained by endoscopy both before and after a fat meal, we evaluated the effect of a fat meal on human intestinal apoB synthesis. Pulse-chase labeling, immunoprecipitation, and sequential radioautography-Western blotting indicated that fat feeding did not change the relative amounts of apoB-100 synthesized in normolipidemic subjects. In contrast, patients with atherosclerosis, hypertriglyceridemia, and a family history of coronary artery disease showed some changes. One patient was identified who synthesized 3 fold more apoB-100 than normals postprandially. This was correlated with the relative abundance of apoB- 100 mRNA detected utilizing a reverse transcriptase-polymerase chain reaction assay on intestinal RNA. These findings suggest that diet- induced atherosclerosis can be due to defective intestinal apoB in some patients with premature coronary artery disease.